The transcription factor cAMP response element binding protein (CREB) has been implicated as a common mediator in the mechanisms of action of drugs of abuse. Our lab has produced a genetically engineered mouse that is lacking the alpha and deltaisoforms of this transcription factor and have shown that while the CREBalphadelta mutant mouse does not find morphine rewarding, this mouse finds cocaine more rewarding than wild type control mice. The objective of this proposal is to examine why there is a different response to morphine and cocaine and to determine if there are differential responses in these mice to other drugs of abuse. Because morphine and cocaine have different sites of action, we propose that there is a differential function and distribution of CREB in the mesolimbic dopamine reward pathway and that administration of drugs of abuse that have similar mechanisms of action will result in similar behavioral results. This hypothesis will be tested by the following aims: 1) Determine if there is a differential distribution and function of CREB in the mesolimbic dopamine reward pathway using Western blots, electrophoretic mobility shift assays and RT-PCR for downstream targets in a region-specific manner. 2) Determine if there is altered regulation of upstream components of the cAMP signal transduction pathways in these mutant mice. 3) Determine the role of CREB in the positive reinforcing properties of drugs of abuse with nicotine and alcohol.